RAGE at Tumor Microenvironment. Looking at Tumor-associated Macrophages

A compell ing body of ev idence has demonstrated that activation of the receptor for advanced glycation endpro du c t s (R AG E) i s r e s p on s i ble f or t r i g ge r i n g a n inf lammatory response and being associated with many clinical entities, including diabetes, neurodegerative diseases, cardiovascular diseases and cancer[1-4]. R AGE is expressed in many tumor cell types where its activation is strongly associated with tumor growth, cell migration and invasion, angiogenesis and resistance to apoptosis. Far beyond its role on some tumor cell activities, R AGE is a lso ex pressed in ma ny t umors in f i lt rat ing cells and thus contributing to the inf lammation-related tumor igenesis[5 , 6]. Of note, tumor microenv ironment represents a particular compartment where most cells not only express RAGE, but also produce many RAGE ligands. One of these infiltrating tumor cells are macrophages. This particular and heterogeneous population of innate myeloid cells, may undergo a polarized activation process once they infiltrated into tumor stroma and thus rendering two distinct polarization states; the “classically activated” type 1 macrophages (M1) and the “alternative activated” type 2 macrophages (M2)[7,8]. The M1 phenotype, can be induced by bacterial products and interferon-γ (IFNγ) and exerts a cytotoxic effect on cancer cells, while the M2 phenotype can be induced by IL-4/IL-13 and promotes tumor cel l grow th and vascular isat ion. Interest ingly, tumor-associated macrophages (TA Ms) constitute the predominant component of leukocytic infiltrate in many solid tumors. TA Ms have the potential to contribute to the earliest stages of neoplasia, smoldering inf lammation at tumor microenvironment (M1 phenotype) and then, as tumor growth up, they are dynamically converted towards a M2 phenotype and exert reduced cytotoxic activities, and promote tumor growth, angiogenesis and immunesuppression. We recently demonstrated that the alarmin H MGB1, w h ich a re abu nd a nt ly e x pressed at t u mor microenvironment, increased the protumoral activities of M2 macrophages by a R AGE-dependent mechanism, thus favoring invasion of tumor cells, the formation of new blood vessel network and the methaloproteinase-9 production[9]. A ll these activities were abrogated by R AGE-targeting knockdown. At f irst glance, these results seem to be paradoxical, considering that first, R AGE activation is associated with an inf lammatory and cytotoxic profile and secondly, M2 macrophages display a wel l-k now n reduced cy totox ic activity. However, R AGE downstream signaling in M2 macrophages has been drifted away from its classical proinf lammatory cascade, just rendering a deactivated NFκB pathway. Although among the different strategies proposed lately to fight cancer, re-education of tumour-associated macrophages from M2 to M1 phenotype seems to be very attractive and potentially a novel approach to cancer intervention from the theoretical point of view. However, there is an urgent need of a more in-deep understanding of cell signaling changes produced by the polarization process in TAMs.

A compelling body of evidence has demonstrated that activation of the receptor for advanced glycation endproduc t s (R AG E) i s re s pon s ible for t r i g ger i n g a n inf lammatory response and being associated with many clinical entities, including diabetes, neurodegerative diseases, cardiovascular diseases and cancer [1][2][3][4] .
R AGE is expressed in many tumor cell types where its activation is strongly associated with tumor growth, cell migration and invasion, angiogenesis and resistance to apoptosis. Far beyond its role on some tumor cell activities, R AGE is also ex pressed in many tumors inf i ltrating cells and thus contributing to the inf lammation-related tumorigenesis [5,6] . Of note, tumor microenv ironment represents a particular compartment where most cells not only express RAGE, but also produce many RAGE ligands.
One of these infiltrating tumor cells are macrophages. This particular and heterogeneous population of innate myeloid cells, may undergo a polarized activation process once they infiltrated into tumor stroma and thus rendering two distinct polarization states; the "classically activated" type 1 macrophages (M1) and the "alternative activated" type 2 macrophages (M2) [7,8] . The M1 phenotype, can be induced by bacterial products and interferon-γ (IFNγ) and exerts a cytotoxic effect on cancer cells, while the M2 phenotype can be induced by IL-4/IL-13 and promotes tumor cell grow th and vascularisation. Interestingly, tumor-associated macrophages (TA Ms) constitute the predominant component of leukocytic infiltrate in many solid tumors. TA Ms have the potential to contribute to the earliest stages of neoplasia, smoldering inf lammation at tumor microenvironment (M1 phenotype) and then, as tumor growth up, they are dynamically converted towards a M2 phenotype and exert reduced cytotoxic activities, and promote tumor growth, angiogenesis and immunesuppression. We recently demonstrated that the alarmin H MGB1, wh ich a re abu nda nt ly e x pressed at t u mor microenvironment, increased the protumoral activities of M2 macrophages by a R AGE-dependent mechanism, thus favoring invasion of tumor cells, the formation of new blood vessel network and the methaloproteinase-9 production [9] . A ll these activities were abrogated by R AGE-targeting knockdown.
At first glance, these results seem to be paradoxical, considering that first, R AGE activation is associated with an inf lammatory and cytotoxic profile and secondly, M2 macrophages display a well-k nown reduced cy totox ic activity. However, R AGE downstream signaling in M2 macrophages has been drifted away from its classical proinf lammatory cascade, just rendering a deactivated NFκB pathway.
Although among the different strategies proposed lately to fight cancer, re-education of tumour-associated macrophages from M2 to M1 phenotype seems to be very attractive and potentially a novel approach to cancer intervention from the theoretical point of view. However, there is an urgent need of a more in-deep understanding of cell signaling changes produced by the polarization process in TAMs.

Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.